试验证明全人scF构建的CAR-T可有效降低CAR-T脱靶毒性
A fully human chimeric antigen receptor with potent activity against cancer cells but reduced risk for off-tumor toxicity
ABSTRACT
Chimeric antigen receptors (CARs) can redirect T cells against antigen-expressing tumors in an HLA-independent manner. To date, various CARs have been constructed using mouse single chain antibody variable fragments (scFvs) of high affinity that are immunogenic in humans and have the potential to mediate “on-target” toxicity. Here, we developed and evaluated a fully human CAR comprised of the human C4 folate receptor-alpha (αFR)-specific scFv coupled to intracellular T cell signaling domains. Human T cells transduced to express the C4 CAR specifically secreted proinflammatory cytokine and exerted cytolytic functions when cultured with αFR expressing tumors in vitro. Adoptive transfer of C4 CAR T cells mediated the regression of large, established human ovarian cancer in a xenogeneic mouse model. Relative to a murine MOv19 scFv-based αFR CAR, C4 CAR T cells mediated comparable cytotoxic tumor activity in vitro and in vivo but had lower affinity for αFR protein and exhibited reduced recognition of normal cells expressing low levels of αFR. Thus, T cells expressing a fully human CAR of intermediate affinity can efficiently kill antigen-expressing tumors in vitro and in vivo and may overcome issues of transgene immunogenicity and “on-target off-tumor” toxicity that plague trials utilizing CARs containing mouse-derived, high affinity scFvs.
嵌合抗原受体(CAR)可赋予T 细胞非MHC依赖性抗肿瘤能力。现有数据表明，多种CAR构建多利用对肿瘤具有高亲和力鼠源单链抗的可变区域（scFv），但这又可能会引发“on-target”毒性。为此，作者开发了并评估了一种利用全人C4叶酸受体阿尔法（αFR）特异性单链抗体构建的CAR。表达这种CAR的人类T细胞在体外培与表达αFR的肿瘤共培养养时，可分促炎细胞因子并表现出细胞毒性。将这种CAR-T回输至人肿瘤小鼠模型中后，研究人员发现和利用鼠源scFv构建的CAR-T相比，这种新型的CAR-T在体内外均表现出相似的抗肿瘤细胞毒性，但对αFR 蛋白表现出更低的亲和力，同时降低了对低表达αFR 蛋白的正常细胞识别。因此，利用全人抗体scFv构建的中等亲和力CAR-T可有效杀伤表达相关抗原的肿瘤细胞，并有效的解决由于使用鼠源scFv构建的CAR引起的脱靶问题。
爱康得生物提醒大家，人源化与全人化是未来CAR-T的发展方向哦
